Oral buccal membrane double-layer controlled release tablet and preparation method thereof

Abstract

The invention provides a double-layer tablet and a preparation method thereof. The double-layer tablet comprises a quick-release layer and a slow-release layer, wherein the quick-release layer comprises an indometacin solid dispersion, a disintegrating agent, a filling agent and a lubricating agent; the sustained-release layer comprises an indometacin solid dispersion, a disintegrating agent, a filling agent, a high-molecular sustained-release polymer and a lubricating agent. The quick-release layer is prepared by adopting a direct powder compression method, and then the raw materials of the slow-release layer are mixed and compressed to the second layer to obtain the double-layer tablet. The preparation process is simple, the medicine is rapidly released to 45% at the initial stage of tablet release, the medicine is continuously and stably released after 20 min, the final release amount reaches 80% or above, no burst release phenomenon exists in the release process, and meanwhile good adhesion time and adhesion force are guaranteed.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular, the present application relates to a kind of indometacin oral buccal film double-layer controlled-release tablets and preparation method thereof, BACKGROUND

[0002] Indometacin is developed and pushed out by American pharmaceutical company Merck from indole drugs, the research goal at that time is to find safer, but equally effective anti-inflammatory drugs than corticosteroids (such as cortisone), for the treatment of rheumatoid arthritis and other diseases. They start from indole acetic acid compounds to carry out structural modification, and finally find indometacin, chemical name: 2-methyl-1-(4-chlorobenzoyl)-5-methoxy-1H-indole-3-acetic acid. Indometacin plays an anti-inflammatory role by inhibiting the activity of cyclooxygenase in vivo.

[0003] Indometacin belongs to BCS II class drugs, special chemical structure and group make it difficult to dissolve in water, after oral administration, it is extremely slow in vivo dissolution, and it is difficult to completely dissolve, resulting in low bioavailability, and the treatment effect is not ideal. The currently marketed dosage forms are mainly tablets, suppositories, capsules and the like, indometacin enteric-coated tablets are a modified preparation, which aims to release the drug at a specific site (the intestine) through coating and controlled-release technology, thereby improving the local concentration and release effect of the drug, however, there are still some problems to be solved:

[0004] 1. Low bioavailability: after oral administration, indometacin is unstable in acidic medium and is prone to amide bond hydrolysis, resulting in reduced bioavailability.

[0005] 2. Short duration of action: the drug release rate of traditional dosage forms is fast, the action time is short, the effective blood drug concentration maintenance time is insufficient, frequent administration is required, and the risk of adverse reactions is increased.

[0006] 3. More side effects: the most common one is gastrointestinal reaction, and long-term use may damage liver and kidney function.

[0007] Therefore, the further optimization of the prescription design and preparation technology of the oral buccal film double-layer tablet can avoid the problems of drug hydrolysis to generate by-products in acidic environment, leading to drug failure, and the disadvantage of delayed release at the initial stage after tablet coating. The drug is rapidly released at the initial stage to achieve rapid therapeutic effect, and then the drug is slowly released continuously, which significantly prolongs the drug release maintenance time. At the same time, the method of directly compressing powder is adopted, which avoids the granulation link, and the use of organic solvents is avoided during the preparation of tablets. SUMMARY

[0008] The present application belongs to the technical field of medicine, and is a double-layer release controlled-release tablet containing active drug indometacin and a preparation method thereof.

[0009] The drug release of the indometacin double-layer controlled-release tablet is composed of a rapid-release layer and a slow-release layer.

[0010] Further, the rapid-release layer of the indometacin double-layer controlled-release tablet is mainly composed of indometacin solid dispersion, disintegrant, filler and lubricant.

[0011] Further, the slow-release layer of the indometacin double-layer controlled-release tablet is mainly composed of indometacin solid dispersion, disintegrant, filler, high-molecular slow-release polymer and lubricant.

[0012] The present application also provides a preparation method of the indometacin double-layer controlled-release tablet.

[0013] The preparation method of the indometacin solid dispersion of the present application is as follows: clear indometacin-ethanol solution is quickly placed into clear povidone K30 aqueous solution, stirring is carried out at 500 rpm under light-proof conditions until the mixed solution appears as a milky suspension, and then the stirring is continuously carried out for 2 h; pre-freezing is carried out in an ultra-low temperature refrigerator (-83 DEG C), and then freeze-drying treatment is carried out, so as to obtain the indometacin solid dispersion.

[0014] The preparation method of the immediate release layer of the indomethacin bilayer controlled-release tablet of the present invention is to sieve the indomethacin solid dispersion, disintegrant, and filler respectively, place them into a 50mL capped centrifuge tube, mix them with a mixer for 5 minutes, and then add magnesium stearate and repeat the above mixing process.

[0015] The preparation method of the sustained-release layer of the indomethacin bilayer controlled-release tablet of the present invention is to sieve the indomethacin solid dispersion, disintegrant, filler and polymer sustained-release polymer, respectively, place them into a 50mL capped centrifuge tube, mix with a mixer for 5 minutes, and then add magnesium stearate and repeat the above mixing process.

[0016] The indomethacin bilayer controlled-release tablets prepared according to the present invention were tested for six months in a constant temperature and humidity chamber at 35±2℃ and 65%±5% relative humidity. The appearance, dissolution and drug content of the tablets did not change significantly compared with 0 months.

[0017] The beneficial effects of this invention are:

[0018] 1. This invention prepares a solid dispersion of indomethacin and povidone K30, making some crystalline drugs closer to an amorphous form and improving the water solubility of the active pharmaceutical ingredient.

[0019] 2. This invention designs a controlled-release system based on a polymer matrix structure. By optimizing the formulation, the gelation properties, adhesion properties, swelling and erosion characteristics of the tablet are controlled to achieve ideal adhesion properties while achieving a relatively ideal release effect.

[0020] 3. The indomethacin bilayer controlled-release tablet designed by the present invention via buccal administration fully combines the efficiency of mucosal administration with the convenience of solid dosage forms. It can avoid adverse phenomena such as the first-pass effect of drugs and hydrolysis of some drugs in acidic environments, which affect the efficacy of drugs. In addition to improving bioavailability, it can also further improve patient compliance. Attached Figure Description

[0021] Figure 1 This is a dissolution curve of the indomethacin bilayer controlled-release tablets of Example 1 of the present invention.

[0022] Figure 2 This is the dissolution curve of the indomethacin bilayer controlled-release tablets in Example 2 of the present invention.

[0023] Figure 3 This is the dissolution curve of the indomethacin bilayer controlled-release tablets in Example 3 of the present invention. Detailed Implementation

[0024] The present invention will be further illustrated below through specific embodiments. For those skilled in the art, modifications, changes and substitutions can be made to these embodiments without departing from the principles and spirit of the present invention. Equivalent substitutions or corresponding improvements made based on the description in the embodiments are still within the protection scope of the present invention.

[0025] Example 1.

[0026] Preparation of indomethacin solid dispersion

[0027] Indomethacin raw material 3g

[0028] Povidone K30 3g

[0029] The above-prescribed amounts of indomethacin and povidone K30 were dissolved in anhydrous ethanol and deionized water, respectively, to form a clear indomethacin ethanol solution and a povidone K30 aqueous solution. Under continuous stirring at 500 rpm, the drug ethanol solution was quickly poured into the povidone aqueous solution. When the mixed solution turned into a milky white suspension, the timer was started and the stirring was continued for 2 hours. After pre-freezing in an ultra-low temperature freezer (-83℃) for 8 hours, the product was taken out and freeze-dried. The resulting product was dried in a 40℃ oven, ground, and passed through a 60-mesh sieve to obtain indomethacin solid dispersion powder.

[0030] Preparation of Indomethacin Immediate-Release Layer

[0031] Taking a single dose as an example (25mg)

[0032] Indomethacin solid dispersion 25mg

[0033] Cross-linked polyvinylpyrrolidone 10mg

[0034] Microcrystalline cellulose 18mg

[0035] Magnesium stearate 2mg

[0036] The above-prescribed amounts of indomethacin solid dispersion, cross-linked polyvinylpyrrolidone, and microcrystalline cellulose were passed through a 60-mesh sieve and placed into 50 mL capped centrifuge tubes. After mixing with a mixer for 5 minutes, magnesium stearate was added and the above mixing process was repeated for later use.

[0037] Preparation of Indomethacin Extended-Release Layer

[0038] Indomethacin solid dispersion 25mg

[0039] Cross-linked polyvinylpyrrolidone 10mg

[0040] Microcrystalline cellulose 18mg

[0041] Hydroxypropyl methylcellulose 20mg

[0042] Magnesium stearate 2mg

[0043] The above-prescribed amounts of indomethacin solid dispersion, crosporopyrrolidone, microcrystalline cellulose, and hydroxypropyl methylcellulose were passed through a 60-mesh sieve and placed into 50 mL capped centrifuge tubes. After mixing for 5 minutes, magnesium stearate was added and the above mixing process was repeated for later use.

[0044] Preparation of indomethacin bilayer tablets

[0045] Immediate-release layer 55mg

[0046] Sustained-release layer 75mg

[0047] Using a double-layer tableting machine, tablets with a diameter of 9.8 mm were compressed using a shallow concave punch with a tablet weight of approximately 130 mg. The physical properties of the tablets were tested during the tableting process.

[0048] Example 2.

[0049] Preparation of indomethacin solid dispersion

[0050] Indomethacin raw material 3g

[0051] Povidone K30 3g

[0052] The above-prescribed amounts of indomethacin and povidone K30 were dissolved in anhydrous ethanol and deionized water, respectively, to form a clear indomethacin ethanol solution and a povidone K30 aqueous solution. Under continuous stirring at 500 rpm, the drug ethanol solution was rapidly added to the povidone aqueous solution. When the mixed solution turned into a milky white suspension, the timer was started and the stirring was continued for 2 hours. The mixture was pre-frozen in an ultra-low temperature freezer (-83℃) for 8 hours, then taken out and freeze-dried. The resulting product was dried in a 40℃ oven, ground, and passed through a 60-mesh sieve to obtain indomethacin solid dispersion powder.

[0053] Preparation of Indomethacin Immediate-Release Layer

[0054] Taking a single dose as an example (25mg)

[0055] Indomethacin solid dispersion 25mg

[0056] Cross-linked polyvinylpyrrolidone 10mg

[0057] Microcrystalline cellulose 18mg

[0058] Magnesium stearate 2mg

[0059] The above-prescribed amounts of indomethacin solid dispersion, cross-linked polyvinylpyrrolidone, and microcrystalline cellulose were passed through a 60-mesh sieve and placed into 50 mL capped centrifuge tubes. After mixing with a mixer for 5 minutes, magnesium stearate was added and the above mixing process was repeated for later use.

[0060] Preparation of Indomethacin Extended-Release Layer

[0061] Indomethacin solid dispersion 25mg

[0062] Cross-linked polyvinylpyrrolidone 10mg

[0063] Microcrystalline cellulose 18mg

[0064] 20mg of polyethylene oxide

[0065] Magnesium stearate 2mg

[0066] The above-prescribed amounts of indomethacin solid dispersion, cross-linked polyvinylpyrrolidone, microcrystalline cellulose, and polyethylene oxide were passed through a 60-mesh sieve and placed into 50 mL capped centrifuge tubes. After mixing for 5 minutes, magnesium stearate was added and the above mixing process was repeated for later use.

[0067] Preparation of indomethacin bilayer tablets

[0068] Immediate-release layer 55mg

[0069] Sustained-release layer 75mg

[0070] Using a double-layer tableting machine, tablets with a diameter of 9.8 mm were compressed using a shallow concave punch with a tablet weight of approximately 130 mg. The physical properties of the tablets were tested during the tableting process.

[0071] Example 3.

[0072] Preparation of indomethacin solid dispersion

[0073] Indomethacin raw material 3g

[0074] Povidone K30 3g

[0075] The above-prescribed amounts of indomethacin and povidone K30 were dissolved in anhydrous ethanol and deionized water, respectively, to form a clear indomethacin ethanol solution and a povidone K30 aqueous solution. Under continuous stirring at 500 rpm, the drug ethanol solution was rapidly added to the povidone aqueous solution. When the mixed solution turned into a milky white suspension, the timer was started and the stirring was continued for 2 hours. The mixture was pre-frozen in an ultra-low temperature freezer (-83℃) for 8 hours, then taken out and freeze-dried. The resulting product was dried in a 40℃ oven, ground, and passed through a 60-mesh sieve to obtain indomethacin solid dispersion powder.

[0076] Preparation of Indomethacin Immediate-Release Layer

[0077] Taking a single dose as an example (25mg)

[0078] Indomethacin solid dispersion 25mg

[0079] Cross-linked polyvinylpyrrolidone 10mg

[0080] Microcrystalline cellulose 18mg

[0081] Magnesium stearate 2mg

[0082] The above-prescribed amounts of indomethacin solid dispersion, cross-linked polyvinylpyrrolidone, and microcrystalline cellulose were passed through a 60-mesh sieve and placed into 50 mL capped centrifuge tubes. After mixing with a mixer for 5 minutes, magnesium stearate was added and the above mixing process was repeated for later use.

[0083] Preparation of Indomethacin Extended-Release Layer

[0084] Indomethacin solid dispersion 25mg

[0085] Cross-linked polyvinylpyrrolidone 10mg

[0086] Microcrystalline cellulose 18mg

[0087] Carbomer 20mg

[0088] Magnesium stearate 2mg

[0089] The above-prescribed amounts of indomethacin solid dispersion, cross-linked polyvinylpyrrolidone, microcrystalline cellulose, and carbomer were passed through a 60-mesh sieve and placed into 50 mL capped centrifuge tubes. After mixing for 5 minutes, magnesium stearate was added and the above mixing process was repeated for later use.

[0090] Preparation of indomethacin bilayer tablets

[0091] Immediate-release layer 55mg

[0092] Sustained-release layer 75mg

[0093] Using a double-layer tableting machine, tablets with a diameter of 9.8 mm were compressed using a shallow concave punch with a tablet weight of approximately 130 mg. The physical properties of the tablets were tested during the tableting process.

[0094] Example Sample Testing

[0095] Example 1: Sample Detection and Property Analysis

[0096] Dissolution should be performed according to the Dissolution and Release Determination Method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II), taking care to avoid light during operation.

[0097] Dissolution conditions: Place the product in a settling basket, use 250 ml of pH 6.8 buffer solution as the dissolution medium, and rotate the machine at 50 rpm. Take 5 ml of solution at 30 min, 60 min, 90 min, 120 min, 240 min, 360 min, and 480 min respectively, and replenish with dissolution medium of the same temperature and volume in a timely manner.

[0098] The dissolution solution of the test sample was taken out at each measurement time point, filtered through a 0.45 μm microporous membrane, diluted with the mobile phase, and the dissolution rate at each sampling point was detected by high performance liquid chromatography to calculate the dissolution rate at each time point.

[0099] Example 1: Detection of Physical Properties of Tablets

[0100] The hardness of the tablets was measured using a hardness tester (SY-6 ND, China).

[0101] Ten tablets of each formulation were randomly weighed on an electronic analytical balance (HZK-FA110, China) and the average weight was determined.

[0102] Tablet Friability Test Method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0923)

[0103] The testing method involves randomly selecting ten tablets, blowing off the powder from the surface, accurately weighing them, placing them in a tumbling barrel, and rotating them 100 times. The tablets are then removed, the powder is removed again using the same method, and they are accurately weighed. The weight loss must not exceed 1%.

[0104] Content test method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0251)

[0105] The test method involves grinding the tablets into a uniform powder using a mortar and pestle, accurately weighing 1 mg, and then making up to 10 ml in a volumetric flask with the mobile phase. The solution is then sonicated and shaken until completely clear. After filtration through a 0.45 μm microporous membrane, the solution is diluted to volume with the mobile phase and detected by high performance liquid chromatography to calculate the drug content of the tablets.

[0106] Adhesion strength was evaluated in vitro using a modified equilibrium method. A 1×1 cm mucosa was soaked in pH 6.8 for 1 hour and then glued to a smooth glass surface, simultaneously attaching a tablet to the bottom of a plastic cap. The tablet was suspended directly above the mucosa, balanced against a tray on the left. After contacting the tablet with the mucosal tissue, a 5 g weight was used to press the tablet against the plastic cap for a period of time. The weight was then removed, and water was added dropwise to another test tray at a uniform rate. Water addition was stopped when the tablet separated from the mucosal tissue, and the weight of the added water was measured to obtain the adhesion strength (g).

[0107] Adhesion time: A 1×1 cm buccal membrane tissue, soaked in pH 6.8 buffer solution for 1 hour, was glued to the side wall near the bottom of the dissolution medium container. A tablet pre-wetted with 1 mL of pH 6.8 buffer solution was placed on the fixed buccal membrane, and then a 5 g weight was placed on the tablet for a period of time. 250 mL of dissolution medium heated to 37°C at pH 6.8 was then added, and the time required for the tablet to detach from the mucosa was recorded.

[0108] Before the swelling and erosion experiment, the initial weight (Wi) of the tablets was recorded, and then the tablets were placed in a pH 6.8 medium at 37 ± 0.5 °C. The experimental method was the same as that for the dissolution experiment. At each predetermined time point, the tablets were removed, and excess surface moisture was carefully removed with filter paper to obtain the wet weight (Ww) of the tablets. The tablets were then dried in an oven at 35 °C until a constant dry weight (Wd) was reached. The swelling rate and erosion rate were calculated by measuring the mass change of the tablets at different time points.

[0109] Example 1 Sample Dissolution Test Results Table

[0110]

[0111] Example 2: Sample Dissolution Detection

[0112] The dissolution rate of the sample from Example 2 was tested according to the dissolution rate test method of Example 1. The test results are shown in the table below:

[0113] Example 2 Sample Dissolution Test Results Table

[0114]

[0115] Example 3: Sample Dissolution Detection

[0116] The dissolution rate of the sample from Example 3 was tested according to the dissolution rate test method of Example 1. The test results are shown in the table below:

[0117] Example 3 Sample Dissolution Test Results Table

[0118]

[0119] Table of Physicochemical Property Test Results for Examples

[0120]

[0121] Example: Swelling and Erosion Detection Results Table

[0122] swelling rate

[0123]

[0124] Erosion rate

[0125]

[0126] Example 1 is the optimal formulation for indomethacin bilayer tablets. The tablets achieve rapid onset of action through rapid drug release in the initial stage, and achieve long-term and stable drug release through slow release in the middle and later stages. Finally, the tablets are administered via buccal membrane, effectively avoiding a series of problems such as the first-pass effect.

[0127] For those skilled in the art, modifications, variations, and substitutions can be made to these embodiments without departing from the principles and spirit of the present invention. Equivalent substitutions or corresponding improvements made based on the descriptions in the embodiments are still within the protection scope of the present invention.

Claims

1. A process for the preparation of a bilayered controlled release tablet of indometacin buccal film, comprising the following steps: Step 1: indometacin drug substance and povidone K30 are treated by anti-solvent-lyophilization to obtain a solid dispersion of indometacin Step 2: the solid dispersion of indometacin, disintegrant, filler, lubricant are mixed uniformly to obtain a fast release layer of indometacin Step 3: the solid dispersion of indometacin, disintegrant, filler, high molecular weight release polymer, lubricant are mixed uniformly to obtain a release layer of indometacin Step 4: the mixture obtained in step (2) is placed in the first hopper of the tablet press for pre-compression, and the mixture obtained in step (3) is placed on the mixture obtained in step (2) for double-layer compression.

2. The method of preparing the indomethacin solid dispersion according to claim 1 is as follows: clear indomethacin ethanol solution is quickly placed into clear povidone K30 aqueous solution, stirring at 500 rpm in the dark until the mixed solution appears as a milky suspension, stirring for 2 h, pre-freezing in an ultra-low temperature freezer (-83 °C) and then freeze-drying to obtain the indomethacin solid dispersion, wherein, The mass ratio of indometacin drug substance to high molecular weight polymer is 1:

1.

3. The fast release layer of indometacin according to claim 1, wherein the solid dispersion accounts for 62-63% of the total weight of the tablet, the disintegrant accounts for 12-13% of the total weight of the tablet, the filler accounts for 22-23% of the total weight of the tablet, and the lubricant accounts for 2.5% of the total weight of the tablet.

4. The release layer of indometacin according to claim 1, wherein the solid dispersion accounts for 49-51% of the total weight of the tablet, the disintegrant accounts for 9-11% of the total weight of the tablet, the filler accounts for 17-19% of the total weight of the tablet, the high molecular weight release polymer accounts for 19-21% of the total weight of the tablet, and the lubricant accounts for 2-2.5% of the total weight of the tablet.

5. The bilayered tablet of indometacin according to claim 1, wherein the solid dispersion accounts for 38-39% of the total weight of the tablet, the disintegrant accounts for 7-8% of the total weight of the tablet, the filler accounts for 13.5-14% of the total weight of the tablet, the high molecular weight release polymer accounts for 15-15.5% of the total weight of the tablet, and the lubricant accounts for 1-1.5% of the total weight of the tablet.

6. The tablet of indometacin according to any one of claims 1-5, wherein the solid dispersion carrier is povidone K30; the disintegrant is cross-linked polyvinyl pyrrolidone; the high molecular weight release polymer is one of carbomer, polyethylene oxide, and hydroxypropyl methyl cellulose; the filler is microcrystalline cellulose; the lubricant is magnesium stearate.

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